A. Field of Invention
This invention relates to a process for producing a tissue transplant construct for reconstructing a human or animal organ, to a tissue transplant construct of this type, and to a use of a tissue transplant construct of this type. The invention relates in particular to a tissue transplant construct for reconstructing the urinary bladder.
B. Description of the Related Art
The urinary bladder consists of the mucosal layer and of the muscle tissue layer. Mucosal cells are urothelial cells which form a mutilayer covering of the interior of the urinary bladder and protect it against urine. The muscle tissue, referred to as detrusor, consist of smooth muscle cells and, located between them, interstitial cells, which comprise fibroblasts or fibroblastic cells. Fibroblastic cells consist of two cell populations, with positive and negative expression of c-kit antibody. The muscle cells are responsible for the contraction, i.e., the emptying of the urinary bladder. The interstitial cells are responsible for transmission of the electrical impulses derived from muscle cells, and thus for the functioning of the muscle cells as a unit.
Reconstruction of the urinary bladder may be necessary because of congenital or acquired disorders such as, for example, meningomyelocele, bladder exstrophy and cloacal exstrophy, traumata, malignant tumors, neuropathic dysfunctions, detrusor instability. Reconstruction of the urinary bladder is effected clinically by using segments of intestine. This is associated with multiple complications such as, for example, infection, incontinence, malignant degeneration, diarrhea, electrolyte disturbance, malabsorption and increased morbidity. It has been proposed to carry out the reconstruction, i.e. the replacement of damaged or diseased regions of a urinary bladder, by means of tissue transplant constructs which are intended to serve as a matrix for regrowth of original tissue. In this connection, the cultivation of patients' own urinary bladder cells on the membrane and thus the in vitro generation of viable bladder tissue has been proposed several times [1, 2, 3]. However, this shows a large number of problems.
In addition, tissue transplant constructs comprising a biological, collagen-containing membrane onto which one or more layers of organ-specific urothelial cells are applied are known for the reconstruction of a human urinary bladder. The outer layer of the urothelial cells is a layer of terminally differentiated tissue cells [4].
However, needed for reconstruction of a urinary bladder also with regard to its physiological function are not only urothelial cells as barrier layer against urine, but also smooth muscle cells in order to enable contraction thereof. However, it has not to date been possible to reconstruct urinary bladder tissue with seeded membranes whose contractility corresponds to that of the natural tissue, because complete generation of muscle cells after implantation has not been achieved. One reason for this is presumably that adult smooth muscle cells lose their more differentiated phenotype in vitro [5, 6]. It is moreover unknown whether smooth muscle cells are in fact able to redifferentiate completely after implantation [6]. On the other hand, the intercellular communication between smooth muscle cells may be impaired through the deficiency of interstitial fibroblastic cells in the tissue transplant construct, possibly leading to a voiding dysfunction after implantation of the construct [7, 8].